EP0248107B1 - Ringsubstituierte alpha-(Alkylaminopropionyl)-thiophen-Derivate, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Zusammensetzungen - Google Patents

Ringsubstituierte alpha-(Alkylaminopropionyl)-thiophen-Derivate, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Zusammensetzungen Download PDF

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Publication number
EP0248107B1
EP0248107B1 EP86112100A EP86112100A EP0248107B1 EP 0248107 B1 EP0248107 B1 EP 0248107B1 EP 86112100 A EP86112100 A EP 86112100A EP 86112100 A EP86112100 A EP 86112100A EP 0248107 B1 EP0248107 B1 EP 0248107B1
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EP
European Patent Office
Prior art keywords
thiophene
chlorothiophene
sec
butylaminopropionyl
alkylaminopropionyl
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EP86112100A
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English (en)
French (fr)
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EP0248107A1 (de
Inventor
Rafael Foguet
Ernesto Forné
Aurelio Sacristán
José A. Ortiz
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Ferrer Internacional SA
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Ferrer Internacional SA
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/28—Halogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom

Definitions

  • the present invention relates to certain thiophene ring-substituted a-(alkylaminopropionyl)-thiophene derivatives, a process for preparing them and pharmaceutical composition containing them.
  • EP-A-196 001 which is a prior art document pursuant to article 54 (3) and (4) EPC relates to different thiophene ring-substituted a-(alkylaminopropionyl)-thiophene derivatives of the general formula (I): wherein X is a group different from hydrogen selected between methyl or chlorine and R is a linear or branched chain-alkyl group having 3 to 4 carbon atoms, and the nontoxic addition salts thereof, as well as to a process for preparing these compounds and to pharmaceutical compositions containing these compounds.
  • One object of the present invention relates to thiophene derivatives selected from:
  • the preferred addition salts are the hydrochlorides.
  • the compounds of the present invention may be prepared according to the following scheme:
  • a-(Bromopropionyl)-thiophene precursors of general formula (II) are obtained by conventional methods in Organic Chemistry; the reaction of propionyl-thiophenes with bromine in a medium composed by an aliphatic-chlorinated hydrocarbon, for example, methylene chloride, chloroform or carbon tetrachloride, are preferred.
  • propionyl-thiophenes are susceptible to be obtained either by acylation of respective thiophenes with a derivative of propionic acid, preferably propionyl chloride, under suitable conditions of Friedel-Crafts' reaction, or by reacting lithium derivatives of respective thiophenes with propionitrile.
  • the compounds of the present invention have an effective antidepressant activity as evidenced by R. D. Porsolt (Immobility behavioural despair test in mice: Arch. Int. Pharmacodyn., 229, 327-336, 1977), which differ from the thiophene ring non-substituted a-(alkylaminopropionyl)-thiophenes, as disclosed in French Patent No. 3414M and British Patent No. 1313150, because these known compounds have anorexic activity devoided of central excitatory action or cardiovascular action, and neuroleptic, tranquillizing and analgesic action respectively. Consequently, the presence of an X group different from hydrogen, selected between methyl or chlorine, in the compounds of formula (I) leads to compounds having a very effective antidepressant action.
  • the compounds of this invention are useful as medicament for treating depressions.
  • the compounds of the present invention mixed with pharmaceutically acceptable carriers can be administered by the oral route in the form of tablets, capsules, coated tablets, syrups, solutions, etc., by injectable route and by rectal route at daily doses ranging from 2.5 to 250 mg/kg.
  • the crude product (21.2 g) is dissolved in 400 ml of dry ethyl ether, cooled with water-ice bath and a dry HCI (g) stream is passed through; the insolubilized hydrochloride (20.0 g) is recrystallized from isopropanol to give 9.5 g (32%) of a white solid, m.p. 208-209°C and analysis correct.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Psychiatry (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)

Claims (7)

1. Substituierte a-(Alkylaminopropionyl)-thiophen Derivative ausgewählt unter:
2-[a-(sek-Butylaminopropionyl)]-4-chlorthiophen,
2-[a-(sek-Butylaminopropionyl)]-4-methylthiophen,
2-[a-(n-Propylaminopropionyl)]-4-methylthiophen,
2-[a-(Isopropylaminopropionyl)]-5-chlorthiophen,
2-[a-(n-Propylaminopropionyl)]-5-chlorthiophen,
2-[a-(sek-Butylaminopropionyl)]-5-chlorthiophen,
4-[a-(Isopropylaminopropionyl)]-2-chlorthiophen,
4-[a-(sek-Butylaminopropionyl)]-2-chlorthiophen
und die nicht-toxischen Säureadditionssalze davon.
2. Verfahren zur Herstellung der Verbindungen gemäß Anspruch 1, dadurch gekennzeichnet, daß ein (a-Brompropionyl)thiophen der allgemeinen Formel II:
Figure imgb0009
worin X für Methyl oder Chlor steht, mit einem Amin der allgemeinen Formel 111:
Figure imgb0010
worin R für n-Propyl, i-Propyl oder sek-Butyl steht, in einem inerten Medium und bei einer Maximaltemperatur von 50°C umgesetzt und falls gewünscht, die freie Base mit einer Säure behandelt wird, um ein nicht-toxisches Additionssalz zu erhalten.
3. Verfahren nach Anspruch 2, dadurch gekennzeichnet, daß Acetonitril als inertes Medium für die Reaktion zwischen 11 und III verwendet wird.
4. Verfahren nach Anspruch 2, dadurch gekennzeichnet, daß ein Äther als inertes Medium bei der Bildung der nicht-toxischen Additionssalze verwendet wird.
5. Verfahren nach Anspruch 2, dadurch gekennzeichnet, daß der Äther Diäthyläther ist.
6. Pharmazeutische Zusammensetzungen mit zumindest einer Verbindung nach Anspruch 1, gegebenenfalls mit pharmazeutischen Trägern und/oder zusätzlichen Adjuvantien.
7. Verwendung der Verbindungen nach Anspruch 1 zur Herstellung von pharmazeutischen Zusammensetzungen zur Behandlung von Depressionen.
EP86112100A 1986-06-03 1986-09-01 Ringsubstituierte alpha-(Alkylaminopropionyl)-thiophen-Derivate, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Zusammensetzungen Expired - Lifetime EP0248107B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ES556311A ES8707505A2 (es) 1986-06-03 1986-06-03 Mejoras en el objeto de la patente de invencion n.541.911 por procedimiento de obtencion de nuevos derivados de alfa-(alquilaminopropionil)-tiofeno sustituidos en el anillo tiofenico
ES556311 1986-06-03

Publications (2)

Publication Number Publication Date
EP0248107A1 EP0248107A1 (de) 1987-12-09
EP0248107B1 true EP0248107B1 (de) 1990-07-18

Family

ID=8491524

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EP86112100A Expired - Lifetime EP0248107B1 (de) 1986-06-03 1986-09-01 Ringsubstituierte alpha-(Alkylaminopropionyl)-thiophen-Derivate, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Zusammensetzungen

Country Status (6)

Country Link
EP (1) EP0248107B1 (de)
JP (1) JPS62286989A (de)
DE (1) DE3672832D1 (de)
ES (1) ES8707505A2 (de)
PH (1) PH25703A (de)
ZA (1) ZA867610B (de)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4874876A (en) * 1988-11-02 1989-10-17 Occidental Chemical Corporation Process for the preparation of 2-(2-thienyl)-ethylamine and derivatives thereof
IT1276738B1 (it) * 1995-06-16 1997-11-03 Erregierre Spa Processo per la preparazione di derivati dell'acido -metil-2- tiofeneacetico

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0196001A1 (de) * 1985-03-20 1986-10-01 Ferrer Internacional, S.A. Thiophenkern-substituierte alpha-(alkylaminopropionyl)-thiophen-Derivate, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Zusammensetzungen

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1217396B (de) * 1963-07-04 1966-05-26 Laboratorie Roger Bellon, Neuilly-sur-Seine (Frankreich) Verfahren zur Herstellung von 1 - (Thienyl-21) - l-oxo-2-amino-propanen
FR2062868B1 (de) * 1969-09-15 1973-08-10 Innothera Lab Sa
FR2453172A1 (fr) * 1979-04-06 1980-10-31 Innothera Lab Sa Nouvelles (thienyl-2) amino-1 butyl cetones, leur procede de preparation et leur application en therapeutique
ES8602744A1 (es) * 1985-03-20 1985-12-01 Ferrer Int Procedimiento de obtencion de nuevos derivados -(alquilamino-propionil)-tiofeno sustituidos en el anillo tiofenico

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0196001A1 (de) * 1985-03-20 1986-10-01 Ferrer Internacional, S.A. Thiophenkern-substituierte alpha-(alkylaminopropionyl)-thiophen-Derivate, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Zusammensetzungen

Also Published As

Publication number Publication date
EP0248107A1 (de) 1987-12-09
ES556311A0 (es) 1987-08-01
PH25703A (en) 1991-09-18
DE3672832D1 (de) 1990-08-23
ZA867610B (en) 1987-06-24
JPH0310625B2 (de) 1991-02-14
JPS62286989A (ja) 1987-12-12
ES8707505A2 (es) 1987-08-01

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